Serotonin (5-HT) is a monoamine neurotransmitter and expresses various physiological actions via a 5-HT receptor. The 5-HT receptor is classified into seven families of from 5-HT1 to 5-HT7. Particularly, the 5-HT2 receptor is known to have three subtypes, 5-HT2A, 5-HT2B and 5-HT2C (Non-patent Reference 1).
The irritable bowel syndrome (IBS) is a disease in which an abdominal pain or an abdominal unpleasantness continues for a prolonged period of time. Based on its symptoms, IBS is classified into a diarrhea type, a constipation type and a mixed type of diarrhea and constipation. In each case, it has been pointed out that there is a causal relation between the morbid state and the amount of 5-HT in blood. For example, there is a reference which points out that increase of blood 5-HT concentration after meal occurs in diarrhea type IBS patients and this is deeply concerned in the morbid state (Non-patent Reference 2).
Currently, though it is at the clinical trial in Japan, a 5-HT receptor antagonist or a 5-HT receptor agonist has been used in Europe and America as a therapeutic agent for IBS. As a therapeutic agent for diarrhea type, alosetron (5-HT3 receptor antagonist) is used in the clinical field, but side effects such as ischemic colitis, constipation and the like have been reported. In addition, as a therapeutic agent for constipation type, tegaserod (5-HT4 receptor agonist) is used in the clinical field in Europe and America, but side effects have also been reported (Non-patent Reference 3 and 4).
In recent years, pharmacological studies on other 5-HT receptor subtypes have also been carried out (Non-patent Reference 5). Regarding the 5-HT2B receptor and 5-HT7 receptor, there are reports which pointed out roles of said receptors in digestive tracts. For example, there are reports stating that the 5-HT2B receptor localizes in human ileum longitudinal muscle and a 5-HT2B receptor antagonistic compound suppresses contraction by 5-HT (Non-patent Reference 6), and that the 5-HT2B receptor localizing in human colon is concerned in the 5-HT-induced contraction at the time of electric stimulation and a 5-HT2B receptor antagonistic compound suppresses it (Non-patent Reference 7).
In addition, there are reports stating that the 5-HT7 receptor localizes in guinea pig small intestines (Non-patent Reference 8) and rat small intestines (Non-patent Reference 9) and is concerned in the peristalsis of guinea pig ileum (Non-patent Reference 10).
Also, in the Patent Reference 1 which was applied by the present applicant and laid open to public after priority date of the instant application, it is reported that a selective 5-HT2B and 5-HT7 receptor dual antagonist is useful in treating IBS. Based on the above, it is expected that a compound having the antagonistic activity for 5-HT2B and 5-HT7 receptors is useful as an IBS treating agent.
In addition, since there are reports stating that a selective 5-HT2B and 5-HT7 receptor dual antagonist is useful in preventing migraine (Patent References 2 and 3), it is expected that a compound having the antagonistic activity for 5-HT2B and 5-HT7 receptors is useful also as an agent for preventing migraine.
As the compound having the antagonistic activity for 5-HT2B and 5-HT7 receptors, there are reports of the following Patent References 1 to 3.
In the Patent References 1 to 3, it is reported that a fluoren derivative represented by the following formula (A) has the antagonistic activity for 5-HT2B and 5-HT7 receptors and is useful in preventing migraine (Patent References 2 and 3) and in treating IBS (Patent Reference 1).
(See said official gazettes for symbols in the formula.)
In addition, as the pyrrole derivatives, there are the following reports.
In the Patent Reference 4, it is reported that a pyrrole derivative represented by the following formula (B) has the androgen receptor antagonism and is effective in treating and preventing hormone-sensitive diseases such as prostatic cancer and the like. However, there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
(See said official gazette for symbols in the formula.)
In the Patent Reference 5, it is reported that a pyrrole derivative represented by the following formula (C) has the cannabinoid type 1 receptor antagonism/inverse agonist action and is effective in treating and preventing eating disorder, obesity, type II diabetes, and the like. However, there is no illustrative disclosure as examples of the compound of the present invention, and there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
(See said official gazette for symbols in the formula.)
In the Patent Reference 6, it is reported that a pyrrole derivative represented by the following formula (D) has the cannabinoid type 1 receptor antagonism/inverse agonist action and is effective in treating and preventing eating disorder, obesity, type II diabetes, and the like. However, there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
(See said official gazette for symbols in the formula.)
In the Patent Reference 7, it is reported that an N,N′-substituted-1,3-diamino-2-hydroxypropane derivative represented by the following formula (E) has the beta selectase inhibitory action and is effective in treating and preventing Alzheimer disease.
However, there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
(See said official gazette for symbols in the formula.)
In Non-patent Reference 11, a method for synthesizing 1-benzyl-5-tert-butyl-N-(2-morpholin-4-ylethyl)-2-phenyl-1H-pyrrole-3-carboxamide is reported. However, there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
In Non-patent Reference 12, it is reported that 1-{[1-benzyl-2-methyl-5-(4-nitrophenyl)-1H-pyrrol-3-yl]carbonyl}-4-methyl piperazine has an antimicrobial activity and is effective for Candida. However, there are no descriptions on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.
In Non-patent Reference 13 which was published after priority date of the present application, a method for synthesizing 5-tert-butyl-N,1-bis(2-morpholin-4-ylethyl)-2-propyl-1H-pyrrole-3-carboxamide, N,1-bis(2-morpholin-4-ylethyl)-5-phenyl-2-propyl-1H-pyrrole-3-carboxamide, 4-(1-{[5-phenyl-1-(2-phenylethyl)-2-propyl-1H-pyrrol-3-yl]carbonyl}piperidin-4-yl)morpholine and 1-{[2-(4-chlorophenyl)-5-ethyl-1-(pyridine-2-ylmethyl)-1H-pyrrol-3-yl]carbonyl}-N,N-diethylpyrrolidine-3-amine is reported. However, there are no descriptions on their 5-HT2B and 5-HT7 receptor antagonistic activities and their efficacy for IBS.
In addition, 1-[(2-chlorophenyl)sulfonyl]-4-{[2,5-dimethyl-1-(2-thienylmethyl)-1H-pyrrol-3-yl]carbonyl}piperazine (CAS Registry No. 878918-78-6) is known as a catalogue compound. However, there is no report on its 5-HT2B and 5-HT7 receptor antagonistic activities and its efficacy for IBS.    Non-patent Reference 1: “Pharmacological Reviews”, (USA), 1994, vol. 46, p. 157-203    Non-patent Reference 2: “Gut”, (England), 1998, vol. 42. p. 42-46    Non-patent Reference 3: “The American Journal of Gastroenterology”, (USA), 2000, vol. 95, p. 2698-2709    Non-patent Reference 4: “The American Journal of Gastroenterology”, (USA), 2003, vol. 98, p. 750-758    Non-patent Reference 5: “Drugs”, (New Zealand), 2001, vol. 61, no. 3, p. 317-332    Non-patent Reference 6: “British Journal of Pharmacology”, (England), 1995, vol. 114, p. 1525-1527    Non-patent Reference 7: “British Journal of Pharmacology”, (England), 2002, vol. 135, p. 1144-1151    Non-patent Reference 8: “European Journal of Pharmacology”, (Holland), 1995, vol. 280, p. 243-250    Non-patent Reference 9: “Life Science”, (Holland), 2001, vol. 69, p. 2467-2475    Non-patent Reference 10: “British Journal of Pharmacology”, (England), 2003, vol. 138, p. 1210-1214    Non-patent Reference 11: “European Journal of Organic Chemistry”, (Germany), 2005, vol. 24, p. 5277-5288    Non-patent Reference 12: “Il Farmaco”, (Italy), 1992, vol. 47, p. 1047-1053    Non-patent Reference 13: “Journal of Combinatorial Chemistry”, (USA), 2006, vol. 8, p. 491-499    Patent Reference 1: International Publication No. 2006/085510 pamphlet    Patent Reference 2: International Publication No. 2005/79845 pamphlet    Patent Reference 3: International Publication No. 2005/80322 pamphlet    Patent Reference 4: US Patent Application Publication No. 2005/0101657 specification    Patent Reference 5: International Publication No. 2004/60870 pamphlet    Patent Reference 6: International Publication No. 2005/108393 pamphlet    Patent Reference 7: International Publication No. 2003/040096 pamphlet